The insulin-like growth factors (IGFs) play an important role in normal growth and development. They also stimulate the growth of a number of human tumors and play a role in the pathogenesis of some complications of diabetes. In addition to their role as mitogens, the IGFs also regulate differentiation and are necessary for cell survival. These effects of the IGFs are mediated through the type I IGF receptor. This receptor is a transmembrane tyrosine-kinase and is similar to the insulin receptor. Activation of the IGF receptor results in the phosphorylation of tyrosine residues both on the receptor and on other proteins involved in IGF signal transduction. Several of these proteins have been characterized but it is clear that important proteins remain unidentified. We have recently found that beta and zetu isoforms of the 14-3-3 family of proteins interact with the IGF receptor and are substrates of the receptor in vitro. Importantly, these proteins do not appear to interact with the insulin receptor. 14-3-3- proteins have been shown to interact with other components of the mitogenic and cell survival pathways and to play a role in growth regulation. The objective of the studies outlined in this proposal is to define the role of 14-3-3 proteins in IGF signal transduction. The specific aims are: 1) to identify the biological response(s) mediated by the interaction of 14-3-3 with the IGF receptor; 2) to characterize the interaction between the IGF receptor and 14-3-3; and 3) to determine the mechanism by which this interaction mediates biological response(s) to the IGFs. The methods to be used include in vitro and cell culture analysis and the yeast two-hybrid system. These studies should provide a better understanding of the mechanism by which the IGFs stimulate their biological effects and how this differs from insulin signal transduction. Such information could be valuable for designing new therapies for the treatment of human diseases.